Depression and Mood and Anxiety Disorders.
Major depressive disorder (MDD) is a common, recurrent and disabling condition marked by significant impairments in social and occupational functioning. MDD is the third leading cause of global disease burden, with annual costs exceeding $50 billion in the U.S. workplace alone. The lifetime prevalence of depression is 17% in the U.S., where more than 1.5 million years/annum are lost to MDD-related disability. Suicide is the 10th leading cause of death in the U.S., and two-thirds of all suicides are committed by individuals with MDD. Despite the availability of a variety of medical approaches, up to 50% of patients do not respond to psychological or pharmacological treatments. In the U.S., standard care results in remission (complete recovery) in only one of three MDD patients. Nearly 40% of patients who do recover relapse back into MDD within two years. This occurs in part because many patients voluntarily abandon antidepressant treatment, partly due to what for them are intolerable side effects. In light of these staggering statistics, it is clear that many unmet needs remain in the treatment and relapse prevention of MDD.
MDD and mood and anxiety disorders (MA) are associated with deficits in attention, executive function, learning and memory. Individuals with MDD or MA are particularly impaired at inhibiting or disengaging attention from negative information, and amplify the significance of personal failure by committing more errors immediately after mistakes. It has been suggested that these deficits play a key role in the emergence and maintenance of negative processing biasing, which has been implicated in the etiology of depression and MA. In addition, broadly generalized deficits in processing speed contribute to these cognitive and social-emotional control abnormalities. Impairments in baseline attention further exacerbate cognitive and social impairments and contribute to the social anxiety and withdrawal that can lead to profound degradation of quality of life.
Behavioral and neuroimaging studies in MDD have revealed dysfunctional cognitive and social control systems, with marked deficits in the dorsolateral prefrontal cortex (DLPFC) and dorsal ACC in the former case, and in the amygdala, rostral anterior cingulate cortex (rACC) and other para-limbic structures in the latter 18. Slower information processing is broadly expressed across cognitive and social-control systems, and within the perceptual and cognitive processing machinery that sub-serves them. Deficits in alertness, a key impairment in MDD, have been attributed to dysfunction within a broad network of regions that include the locus coeruleus (LC) in the brainstem as well as medial prefrontal and inferior frontal-parietal cortical areas, predominantly in the right hemisphere. The LC synthesizes norepinephrine, an excitatory neurotransmitter intimately involved in arousal. LC neurons widely innervate and normally amplify responses in the forebrain, with especially strong effects in frontal areas that are dysfunctional in MDD. Importantly, these same areas—most notably the amygdala, inferior frontal-parietal cortex and medial prefrontal regions—project back to the LC, regulating its activity. Metabolically down-regulated cells in the LC in MDD patients are reduced in sizes and numbers, and have greatly dis-elaborated cortical terminal projections. Sizes, metabolism and terminal distributions of LC neurons are all correlated with depression severity, suicide risk, and other life-quality variables.
In spite of a myriad of psychological and pharmacological therapies for MDD, there is still no effective treatment for a large proportion of patients. When treatments do help overcome depressive symptoms, underlying neurobehavioral impairments (e.g., processing speed, cognitive control processes, novelty seeking) commonly remain uncorrected. In addition, reduced cognitive control and abnormal post-error adjustments have been described in individuals with current and past MDD, in patients with elevated dysphoria, and in psychiatrically healthy individuals carrying genetic variants linked to MDD risk, suggesting that these deficits represent core MDD vulnerabilities.
In addition to their limited efficacy for many patients, long-term use of antidepressant medication is expensive, and often results in unwanted side effects. Problems arising from drug withdrawal and justifiable fear of relapse promote long-term—and not infrequently, life-long—drug usage. Psychotherapy (e.g., cognitive behavioral therapy that is usually focused on coping with environmental stressors, cognitive restructuring of negative thoughts, and ‘consciously elevating’ mood) is a more benign treatment approach, but given the prevalence of low arousal states and dysphoria in MDD, compliance can be poor, treatment failure rates again approach 50%, and relapse is common.
From a neuroscience perspective, MDD originates as an experience-driven distortion in the processes of the ‘plastic’ human brain. Psychotherapy treatments have focused on the reduction of the psychological traumas, distresses and anxieties that (among other impacts) result in a dysregulation of the systems that control baseline levels of alertness and attention as well as cognitive control and social-emotional processes. Pharmacological treatments increase the circulating levels of modulatory neurotransmitters that are dysregulated as a consequence of neurological distortions in the arousal and cognitive control centers in the forebrain attention network. Neither treatment fully addresses the complex, emergent neurological distortions characteristic of MDD. Even when effective, standard treatments require long-term if not life-long medication or behavioral therapy, and leave the patient with a strong risk of illness recurrence.
Traumatic Brain Injury.
About one in five Americans incur one or more ‘mild’ or ‘moderate’ traumatic brain injuries that shall bring them to a hospital emergency room or clinic sometime over the course of their lifetimes. About 1.7 million such injuries, sine qua non with diffuse brain damage, are reported in the U.S. each year. Studies in animal models and in human populations have shown that the neurological impacts of such injuries are cumulative. For example, a head injury that results in a concussion increases the probability that an equivalent second blow to the head will induce another concussion; that second concussion can be induced by a substantially weaker subsequent blow; and repeated concussive injuries generate progressively more severe and more enduring behavioral and neurological expressions of broadly distributed brain damage.
Some populations are at especially high risk for more-severe or repeated head injuries. Approximately 300,000 of the 1.6 million men and women who have served in the armed forces in Iraq and Afghanistan, have incurred a TBI; more than 90% of those injuries are categorized as falling within the ‘mild’ to ‘moderate’ part of the clinical spectrum. In the very hazardous physical environment of the Iraq/Afghanistan, about one in three of these individuals have suffered repeated TBIs.
Remarkably, up to about 80% of TBI soldiers and veterans were subjected to blast injuries, which have a high incidence for generating diffuse brain damage. The pressure waves generated by nearby explosions can generate vacuolization (thousands of tiny foci of damage) and induce diffuse damage of axons in both fiber tracks and ‘gray matter’ throughout the brain. The neurological consequences of such injuries can be long enduring, and can affect almost every aspect of brain function. Many tens of thousands of Iraq/Afghanistan veterans have neurobehavioral deficits attributable to blast injuries that can be expected to degrade their ability to function and thrive in the military, and in their post-military civilian lives.
In the US civilian population, about half a million individuals incur a medically-reported concussive injury arising from sports or leisure activities each year. While the single most common cause of a concussive TBI in the civilian population is a bicycling accident, a more serious medical challenge arises from contact sports like boxing, hockey, American football, lacrosse or soccer, in which there is a high probability of repeated brain injury. Studies using sensors mounted in the helmets of American football players, for example, document about a thousand potentially-brain-damaging blows incurred through a high-school or college career for a typical individual American football player. It should be noted that there has been a long-standing presumption that head blows that do not result in concussion present little risk for an athlete, but many animal studies and more-current human studies challenge this proposition. Clear evidence of physical brain damage can be recorded in non-concussed collegiate football players through the course of a playing season. There are professional and collegiate players who acquire a head injury-induced form of early senility who had little or no history of concussions during their playing careers. For a professional football player, cumulative brain injuries almost certainly account for their nearly 20-fold increase in their risks for early-onset Alzheimer's disease. Years of added risk portending an earlier onset of senility appear to result from engagement in any contact sports to the level of a professional or collegiate athlete.
Traumatic brain injuries commonly induce other neurological problems that can further degrade cognitive abilities, and the qualities of life of injured individuals. The majority of TBI patients have post-injury sleep disruption, a problem that can be long enduring. Most have recurring headaches that can plague the TBI sufferer long after their injury. Diffuse brain injury generates abnormal, destabilizing brain activities not infrequently expressed as epileptiform ‘sharp spikes’, or less commonly, by emergent frank epilepsy. A TBI sharply increases the risks of onset of major depressive disorder. Repeated head trauma can result in a neurodegenerative condition called ‘chronic traumatic encephalopathy’ that foretells Alzheimers-like pathology emerging at a young age. As noted earlier, the occurrence of a TBI very significantly shortens the predicted time to onset of Alzheimer's Disease itself. Finally, TBIs arising from a traumatic experience—or in individuals like military veterans, law enforcement officers or health care professionals who might be exposed to repeated traumatic events—are often accompanied by post-traumatic stress disorder (PTSD). Given the overlap in the neurological expressions of PTSD and TBI, diffuse brain injury very substantially increases the probability that PTSD will arise in an individual who has experienced, or subsequently experiences disturbing events. Co-morbid PTSD significantly increases the TBI patient's neurological burden and cognitive impairments, and very significantly impedes their passage back to a normal, stable and productive life.
A number of these problems emerge and grow after the TBI incident, indicating that damage sets destructive change processes in motion that can progressively amplify dysfunction. Headaches, neurological instability, depression, chronic traumatic encephalopathy, PTSD and other associated sequelae can all contribute to what can be growing problems for a traumatically brain injured individual.
Diffuse traumatic brain injuries induce immediate, widely distributed damage to axonal connections in the brain, and to both subcortical and cortical “gray matter.” The physical blow or blast appears to result in breakage of the stiff microtubules that transport nutrients, neurotransmitters and other materials in axons, supporting axon and terminal (synapse) vitality. As a result of this and other damage, there is a significant diffuse loss of axonal projections and synapses. The disruption of axonal transmission and the local swelling and degeneration of axons manifest thousands to millions of these “micro-damage” events in the human brains of a typical TBI-affected patient, with the regions of maximum damage roughly associated with the domains of most-significant neurobehavioral losses that result from the trauma. In a healthy, young brain, there can be substantial physical recovery from these losses, in the sense that axonal swelling and dieback can recover after the initial injury. However, losses in connectivity incurred by the TBI degrade local brain connectivity and reduce connectional reliability, and greatly increase intrinsic brain process “noise” (neuron network “chatter”).
Although there is substantial individual variability in this expressed pathology, damage relatively predictively and disproportionately affects certain neuronal systems and processes. For example, changes in blood perfusion patterns, alterations in resting state connectivity, and the documentation of distortions in neurological responses evoked by specific explicit behaviors known to be affected by “mild” or “moderate” TBI record the most prominent physical and functional changes in the subcortical caudate nucleus, thalamus and cerebellar vermis, and in middle and lateral anterior frontal cortex, the superior temporal cortex and the posterior cingulate cortex. At the same time, a large body of evidence has shown that the functionality and sustained connectivity of these specific brain areas are strongly dependent on the integrity of the machinery and the quality of the information at “lower levels” in the complex neurological systems that feed them—indicating that the recovery of the physical integrity and the functionality of these systems represent the real therapeutic targets.
Most civilian and military TBI patients have speed-of-processing deficits. Such deficits, grossly impacting the efficiency of neurological operations in recognition and responding, are associated with that increase in “noise” (“chatter”) in the TBI brain, with weakened inhibitory processes affecting widely distributed brain areas. Again, the microtrauma-induced damage to axonal projection pathways and the reduction of elaboration of connectivity within brain networks is the probable primary source of this increased chatter.
A large proportion of patients have attention deficits expressed by lowered baseline levels of arousal or attention, and by impairments in selective and sustained attention. A heightened susceptibility to disruption of attention by distractors often adds to the TBI patient's difficulties at staying on task in attention- and memory-demanding behaviors. Sleep regulation deficits also stem from this dysregulation of arousal, attention control and distractor control processes associated with TBI.
Many individuals with TBIs have deficits in working memory, memory span, and delayed recall. Deficits are sometimes not evident on standardized testing, but are revealed when the memory task engages divided attention or involves multi-tasking, or is evaluated in more-cognitively-demanding task scenarios.
Working memory contributes importantly to “cognitive control” abilities; deficits in these higher-order cognitive control processes have been repeatedly documented in TBI. Not surprisingly, those deficits in “cognitive control” or “executive control” have been correlated in different studies with both processing speed and working memory deficits. In this domain of cognitive control, individuals with TBI often have special problems in reward discounting and in associated impulse control and aggression that almost certainly contribute to their greater risks for succumbing to substance abuse and other addictive behaviors. These deficits are especially marked in individuals with co-morbid PTSD.
Problems in social cognition and social control can be especially impactful for an individual with TBI because a degradation of social cognition can contribute so importantly to employment success, and to the effective reconnection of the brain-injured individual with their partners, families and communities. About half of individuals with TBIs have difficulties in recognizing and responding appropriately to facial affect or gesture-expressed emotions; a larger proportion have problems in higher-order aspects of social cognition that impact interactive social skills, attachment and empathy.
Childhood Abuse.
Stressed and abused children who endure multiple negative factors in their social environments express altered levels of cortisol and noradrenaline in their bodies and brains. While the cortisol/noradrenaline responses to stress underlie our effective somatic and neurological responses to danger/threat that help assure our survival, unabated stress (cortisol & noradrenaline release) has enduring negative functional and physical impacts on elemental learning processes and on the modulatory control machinery governing learning-induced plasticity in their brains. High circulating levels of noradrenaline and the delayed maturation of inhibitory processes in the brain contribute to a greatly elevated risk of onset of an anxiety syndrome. At the same time, paradoxically, the brain's own production of noradrenaline, dopamine, serotonin and acetylcholine—all key “neuro-modulators”—are down-regulated, which, paradoxically, results in a weakened resilience against the later onset of a depressive disorder.
There are more than two million Americans with a history of abuse in which these contrary neurological effects ultimately cycle from a period of down- to up- to down-regulation of these processes, expressed as an emergent bipolar disorder. Moreover, many stressed and abused children have attention control deficits encompassing problems with both a) inattentiveness and b) ‘hyperactivity’ associated with impulsivity and difficulty in controlling responses to distractors. These changes obviously relate to the down-regulation of intrinsic noradrenaline release and to blunted responses to cortisol release that stem from their strong engagement of the HPA axia in periods of stress or abuse. Furthermore, most distressed and abused children have distortions in reward-weighting processes in their brain that, combined with their cognitive control deficits and impulsive responding, put them at high risk for the later emergence of destructive addictive and compulsive behaviors.
Also, most distressed and abused children have deficits in social cognition that impair social interaction success and weaken their development of attachments and empathy. These deficits, which contribute strongly to a degraded quality-of-life, also foretell a greatly increased probability that societal alienation shall ultimately result in criminal offense and incarceration. They frustrate the chances that a child that has been subjected to ongoing stress or abuse shall have a thriving, social, successful older life